In a small study involving organs from 34 donors, diabetic patients taking incretin drugs had a 40% increase in pancreatic mass and a six-fold increase in beta cell mass compared with diabetes patients not on the drugs, Alexandra Butler, MD, of the University of California Los Angeles, and colleagues reported online in Diabetes.

"These findings lend additional weight to concerns regarding the effects of long-term GLP-1 related therapy with respect to both unintended proliferative actions on the exocrine pancreas and now also a possible increased risk of neuroendocrine tumors," they wrote.

Michael McDermott, MD, of the University of Colorado, who was not involved in the study, told MedPage Today that the results are "provocative" and will likely have an impact on clinical use.

"On the one hand, it shows that we may someday be able to regenerate appropriately functioning beta cells in patients with diabetes," he said. "On the other, it is worrisome that the current incretin therapies may have a less specific proliferative effect that could result in pancreatic neoplasms."

He cautioned that clinically, physicians haven't seen a significant increase in actual pancreatic neoplasms, "so we must take this data seriously, but interpret it carefully."

There's been longstanding controversy about the effects of GLP-1 based therapies, known as incretin therapies, on the pancreas. Concerns came to the forefront after an earlier paper by the Butler group at UCLA found an increased risk of pancreatitis with the drugs in an analysis of FDA adverse event reporting data.

That report was followed by a recent study in JAMA that showed a higher risk of hospitalization for pancreatitis among those on the drugs.

The FDA announced earlier this month that it was looking into the relationship between incretin drugs and pancreatic disease on the basis of unpublished data -- which turned out to be those from the present study.

The European Medicines Agency has also announced an investigation into the findings from the Butler group.

For this study, Butler and colleagues examined the pancreas of various organ donors: those with type 2 diabetes who had incretin therapy (eight), diabetics on other therapies (12), and controls without diabetes (14).

Most of those in the incretin group (seven of eight) had been treated with sitagliptin (Januvia) and one was treated with exenatide (Byetta, Bydureon).

The 40% increase in pancreatic mass among diabetes patients treated with incretin therapy was significant at P<0.05.

The six-fold increase in beta cell mass among those on incretins compared with a 55% drop in beta cell mass for diabetics not on incretins (P<0.01).

Although it is typical for diabetic patients to lose beta cell mass, the researchers cautioned that the increased mass isn't necessarily a good thing with incretin therapy.

"At first sight, the increase in beta cell mass with incretin therapy in diabetes would appear to be an exciting finding in relation to the potential for disease reversal," they wrote. "Unfortunately, these insulin-expressing cells are presumably not functionally mature since the incretin-treated individuals still had diabetes."

Those on incretins also had increased exocrine cell proliferation (P<0.0001) and dysplasia, particularly in the form of pancreatic intraepithelia neoplasia (P<0.01) -- a finding consistent with earlier work that "GLP-1 induces proliferative signaling in human pancreatic duct epithelial cells," they wrote.

They also noted increased alpha cell hyperplasia, three glucagon-expressing microadenomas, and a neuroendocrine tumor in diabetic patients on incretins. There were no neuroendocrine tumors or glucagon-producing microadenomas among nondiabetics or among diabetics not on incretins, they added.

The study was limited because most patients were taking sitagliptin, a DPP-4 inhibitor that works by blocking an enzyme that breaks down GLP-1. The one patient treated by exenatide showed a "comparable pattern of changes to those observed in sitagliptin individuals, implying that a direct action of GLP-1 is likely involved," but Butler and colleagues noted that in order to "fully address this question, it will be important to obtain more pancreata from individuals who have been treated with [other] GLP-1 mimetic therapies."

"In addition to the surveillance previously recommended for the potential association of GLP-1-based therapy and pancreatic cancer risk, the current data imply that surveillance for a possible increased risk of pancreatic neuroendocrine tumors is warranted," they concluded.

McDermott agreed that most diabetes providers will need to see more research before they "stop using this class of medications," but added that he suspected it would "prompt some providers and patients to avoid the incretin class of drugs in the future."

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the Hillblom Foundation, and the Peter and Valerie Kompaniez Foundation.

The researchers reported no conflicts of interest.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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